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Cardiovascular Research 2001 52(1):95-102; doi:10.1016/S0008-6363(01)00361-3
© 2001 by European Society of Cardiology
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Copyright © 2001, European Society of Cardiology

Activation and inactivation of cAMP-response element-mediated gene transcription in cardiac myocytes

Frank U Müller*, Peter Bokník, Jörg Knapp, Bettina Linck, Hartmut Lüss, Joachim Neumann and Wilhelm Schmitz

The Institute for Pharmacology and Toxicology, University of Münster, Domagkstr. 12, D-48149 Münster, Germany

* Corresponding author. Tel.: +49-251-835-5503; fax: +49-251-835-5501 mullerf{at}uni-muenster.de

Objective: Chronic β-adrenergic stimulation of the cAMP-dependent signalling pathway is implicated in functionally relevant expressional changes in congestive heart failure. We studied activation and inactivation of the cardiac gene transcription mediated by the cAMP-response element (CRE) and the CRE-binding protein (CREB) as an important mechanism of a cAMP-dependent gene regulation. Methods: We investigated the transcriptional activation by forskolin, an activator of the adenylyl cyclase, in chick embryonic cardiomyocytes transfected with a CRE-controlled luciferase construct in comparison to the phosphorylation and expression of CREB determined on immunoblots. Results: Forskolin (10 µmol/l; 8 h) increased CRE-mediated transcription and phosphorylation of CREB 13- and 1.5-fold, respectively. The phosphorylation was further elevated in combination with cantharidin, an inhibitor of type 1+2A protein phosphatases. The transcriptional response to forskolin was desensitized by pretreatment with forskolin (1 µmol/l; 24 h) while CREB phosphorylation was increased. In forskolin-pretreated cells, total CREB protein levels were decreased. Cantharidin did not restore the attenuated transcriptional response. Conclusions: In cardiomyocytes, there is an activation of the CRE-mediated gene transcription by forskolin that is attenuated after prolonged stimulation, and this attenuation is not dependent from a dephosphorylation of CREB. We suggest that attenuation of the CRE-mediated transcription through chronic stimulation of the cAMP-pathway, e.g. by elevated catecholamines, contributes to the altered expressional regulation in congestive heart failure.

KEYWORDS Adrenergic (ant)agonists; Gene expression; Heart failure; Myocytes; Protein phosphorylation


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